Although the classical role of peroxisome proliferator-activated receptor ? or ? (PPAR?) is to regulate genes involved in fatty acid synthesis, PPAR? is highly expressed in the CNS and it participates in many brain functions including myelination. Being a nuclear hormone receptor, PPAR? needs ligand(s) for its activation and nuclear translocation. Although there are many synthetic ligands of PPAR?, nothing is known about the physiological activation of PPAR? by endogenous ligands in the brain. Therefore, we have identified three possible physiological ligands [1,3-di-tert-butylbenzene (DBB); 2,4-di-tert-butylphenol (DBP); hexadecanoic acid, methyl ester (HAM)] of PPAR? from nuclear extracts of mouse cerebellum. Here, by using in silico interaction studies, time-resolved FRET analyses, thermal shift assay, site-directed mutagenesis, and mass spectrometry, we will characterize whether these physiological molecules are true ligands with PPAR?. Furthermore, we would like to examine whether these cerebellar ligands exhibit promyelinating effect via PPAR?. A positive outcome of this grant proposal will highlight the discovery of novel cerebellar ligands of PPAR?, allowing us to develop cerebellum-based drugs in the future to promote remyelination in demyelinating disorders.